Talk abstracts
Talk on Tuesday 04:45-05:00pm submitted by Ruohan Wu
Genetic and pharmacological modulation of T lymphocytes polyamine metabolism as a therapeutic approach for autoimmune disease
Ruohan Wu (MCDB. OSU), JN Rashida Gnanaprakasam (Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Childrens Hospital), Tingting Wang, Lingling Liu (Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Childrens Hospital), Xuyong Chen, Yuqing Shen (Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Childrens Hospital), John Sherman (MCDB. OSU), Ruoning Wang (Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Childrens Hospital)
Abstract:
Objective: T lymphocytes are a major component of adaptive immunity that offers key immune surveillance against pathogens and cancer cells. The dysregulation of T cell function is associated with many pathological conditions include autoimmune diseases and cancers. Upon antigen stimulation, T cells rapidly engage glucose and glutamine catabolic programs, which is largely orchestrated by the proto-oncogene MYC, to meet the markedly increased demands on ATP, antioxidants and metabolites that are biosynthetic precursors. MYC also regulates ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine (PA) biosynthesis during T cell activation and differentiation. PA is among one of the most tightly regulated metabolite groups in T cells upon T cell activation. Both de novo biosynthesis of PA and uptake of PA from the extracellular environment are required for maintaining cellular PA homeostasis. Hence, we propose that polyamine homeostasis which is tightly controlled by MYC-dependent polyamine de novo biogenesis and extracellular uptake is essential for T cell activation and differentiation, therefore, polyamine pool represents a novel therapeutic target for T cell-mediated autoimmune disease.
Methods: in vitro T cell activation, proliferation, differentiation assays. qPCR. Immunoblot. In vivo mouse model of adoptive cell transfer and experimental autoimmune encephalomyelitis (EAE).
Results & Conclusion: In vitro elimination of T cell polyamine pool by blocking biosynthesis and uptake inhibits T cell proliferation and altered differentiation by reducing pro-inflammatory lineage commitment while enhancing anti-inflammatory lineage commitment. In vivo inhibition of PA biosynthesis alone has no effect on EAE symptom development while blockage of both synthesis and uptake shows a protective effect supporting the therapeutic potential of targeting polyamine metabolism in treating T cell-mediated autoimmune disease.
References:
Wang, R., et al., The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity, 2011. 35(6): p. 871-882.
Keywords: Polyamine metabolism, T cell, T cell-mediated autoimmune disease